ABSTRACT Lung cancer is the second most common cancer and the leading cause of cancer-related death for both men and women for all major racial/ethnic groups in the United States. Smoking is the strongest risk factor for lung cancer. However, in the Multiethnic Cohort study (MEC), we showed that even when accounting for smoking history (quantity, duration and quit rates), African Americans and Native Hawaiians had higher risk of disease and Japanese Americans and Latinos had a lower risk when compared to whites. Lung cancer is a heterogeneous disease with four major histologic cell-types and racial/ethnic disparities persists across all cell- types. We have reported on the mechanisms contributing to these differences in smoking-related lung cancer risk, we examined lifestyle and health behaviors, internal biologic dose of tobacco smoking and its carcinogens, as well as the influence of smoking on DNA methylation of blood leukocytes across a multiethnic population. In a recent study reporting on gene expression profiles to compare lung ADC from African Americans and whites, they found that there were differences in tumor biology for lung ADC tumors from African Americans compared to whites, suggesting that racial/ethnic disparities may be reflected in differences in the underlying lung tumor biology. However, to date, a comprehensive molecular study that includes other minority populations has not yet been conducted. Thus, the goal of this proposal is to molecularly profile the most common lung cancer cell-type, ADC, from five racial/ethnic groups in the MEC to comprehensively examine for racial/ethnic differences in tumor biology that may be contributing to the racial/ethnic disparities. For our first aim, we will conduct a comprehensive genome-wide DNA methylation and transcriptome analysis for differences by race/ethnicity using lung ADC tumor tissue from 750 multiethnic lung cancer cases (African Americans, Latinos, Native Hawaiians, Japanese Americans, and whites). We will adjust for potential confounders such as age, sex, race/ethnicity, smoking status, and tumor stage. For our second aim, we will examine the association for DNA methylation and transcriptomic profiles of lung ADC tumors with lung ADC survival and effect modification by race/ethnicity. For the third aim, we will examine whether DNA methylation and transcriptomic profiles mediate the association between race/ethnicity and lung ADC survival. In addition, we will integrate DNA methylation, transcriptomic, risk factor, and death data to identify novel lung cancer subgroups associated with disease survival. The strengths of this study include 1) large-scale comprehensive molecular study design, 2) utilization of the high-quality resources within the MEC, and 3) the multi-disciplinary investigative team. Findings from this study will provide information on the biological mechanisms underlying the racial/ethnic disparities and evidentiary basis for the development of new personalized treatment targets and strategies to mitigate racial/ethnic disparities in lung cancer.